Résumé
Objectifs : Les implants mammaires pour fins esthétiques ne sont pas associés à une
augmentation de risque de cancer du sein, mais les variations du risque selon les caractéristiques des implants ne sont pas encore bien comprises. De plus, le risque de cancer à d’autres sites que le sein doit être clarifié. Cette étude a pour objet de combler ces lacunes.
Méthodes : Cette étude présente une analyse de 10 ans de plus de suivi d’une étude de
cohorte de femmes ayant reçu soit des implants mammaires pour fins esthétiques (n=24 558) ou une autre chirurgie esthétique (15 893). Plus de 70% de la cohorte a été suivi pour plus de 20 ans. L’incidence du cancer parmi le groupe avec implants mammaires a été comparée au groupe contrôle avec des modèles de Poisson multivariés ainsi qu’aux femmes de la population générale en utilisant le Rapport Standardisé d’Incidence (RSI).
Résultats : Les femmes avec des implants mammaires avaient des taux réduits de cancers
du sein et de l’endomètre comparativement aux femmes avec une autre chirurgie esthétique. Les implants mammaires en position rétro-glandulaire étaient associés à un taux réduit de cancer du sein comparativement aux implants en position rétro-pectorale (Rapport de Taux d’incidence = 0,78, IC à 95% = 0,63-0,96). Un taux 7 fois plus élevé de cancer du sein a été observé (RT d’incidence = 7,36, IC à 95% = 1,86-29,12) dans les cinq premières années après la chirurgie pour les femmes ayant des implants en position rétro-glandulaire avec enveloppe au polyuréthane comparativement aux femmes ayant des implants en position rétro-glandulaire sans polyuréthane, mais le RT d’incidence diminuait progressivement avec le temps (valeur p de tendance = 0,02). Nous n’avons observé aucune augmentation du risque de formes de cancer plus rares parmi les femmes avec implants mammaires.
Conclusion : Une réduction de l’incidence de cancer du sein a été observée pour les
femmes avec implants mammaires en position rétro-glandulaire relativement à la position rétro-pectorale. L’augmentation possible de l’incidence de cancer du sein pour les implants avec enveloppe au polyuréthane peu après la chirurgie nécessite d’être clarifiée.
Abstract
Objectives: Cosmetic breast implants are not associated with increased breast cancer
incidence, but variations of risk according to implant characteristics are still poorly understood. As well, the assessment of cancer risk for sites other than breast needs to be clarified. The purpose of this study was to fill these research gaps.
Methods: This study presents an extended analysis of 10 more years of follow-up of a
large Canadian cohort of women who received either cosmetic breast implants (n=24,558) or other cosmetic surgery (15,893). Over 70% of the implant cohort was followed for over 20 years. Cancer incidence among implant women was compared to those of controls using multivariate Poisson models and the general female population using the Standardized Incidence Ratios (SIRs).
Results: Women with breast implants had reduced rates of breast and endometrial cancers
compared with other surgery women. Subglandular implants were associated to a reduced rate of breast cancer compared to submuscular implants (Incidence Rate Ratio (IRR) = 0.78, 95% CI= 0.63-0.96) and this reduction persisted over time. We observed a 7-fold increased rate (IRR = 7.36, 95% CI= 1.86-29.12) of breast cancer in the first five years after the date of surgery for polyurethane-coated subglandular implant women compared to other women with subglandular implants without polyurethane coating, but this IRR decreased progressively over time (p value for trend = 0.02). We also observed no increased risk of rarer forms of cancer among augmented women.
Conclusion: A reduction in breast cancer incidence was observed for women with
subglandular implants relative to women with submuscular implants. Possible increase of breast cancer incidence shortly after breast augmentation with polyurethane implants needs to be verified.
Introduction
Cosmetic breast implants have been the subject of numerous investigations of the long term risk of mortality and cancer incidence (1-3). Early concerns focused on their potential carcinogenic effect, especially for breast cancer, because of the possible link between silicone and such disease (4). Consequently, silicone gel-filled breast implant (SGFIs) were removed from the market in the United-States and Canada in the early 1990s, but were reapproved for general cosmetic use in both countries in 2006 because later studies showed no carcinogenic effect of silicone (1-3;5). Indeed, a recent report from the U.S. Food and Drug Administration concluded that cosmetic breast implants are not associated with increased breast cancer incidence (3). However, examining long term health risks associated with these devices is still important as adverse health effects may only occur after a long latency period.
More recently, breast implants have been studied in an attempt to evaluate variations of breast cancer risk according to specific implant characteristics. Results across epidemiological studies that collected information on implant characteristics have been inconclusive (6-11). This paucity of evidence may be due to the relatively limited number of breast cancer cases across studies. Common implant characteristics include the type of implant (saline or silicone gel-filled implants (SGFIs)), the placement of the implant (submuscular or subglandular), the implant fill volume and the implant envelope (polyurethane coated or not). Polyurethane foam-covered breast implants were withdrawn from the market in 1991, both in the United-States and Canada, when a report showed that polyurethane could degrade into significant quantities of 2,4-diaminotoluene (2,4-toluene diamine) (TDA) (12) which has been recognized as an animal carcinogen and potential human carcinogen (12). However, polyurethane implants are still used in Europe and South America. Little is known to date about the long term health effects in humans of such implants. Evaluation of the potential cancer risk associated with these devices, especially in the subglandular position because of proximity to breast tissue, is important. Furthermore, the concern raised in our earlier study of a possible two-fold increased risk of breast cancer for women with polyurethane implants in the subglandular position needs to be clarified over a longer period of follow-up (7).
A number of epidemiological investigations have evaluated the relationship between breast implants and the incidence of cancer at sites other than the breast (1;6;7;13-18). The findings from these studies have been largely negative when women with implants were compared with women who had other cosmetic surgeries (6;7;17) or with women from the general population (6;7;14;16). The absence of a positive association could be due to lack of effect but also it could be explained by methodological limitations such as the small number of identified incident cancers and/or short follow-up (18). For instance, few studies had a follow-up time over 30 years (6;13;15). However, some studies reported an increased risk for some types of cancer when compared with general population estimates including the brain (19), lung (13;15;19;20), vulva (14) and cervix (18). The assessment of cancer incidence at sites other than the breast was reported in our earlier study (7). Although elevated or reduced risks for some types of cancers were observed, these results were not statistically significant. Moreover, a recent report by the FDA as well as review articles recommended that the risk of hematopoietic malignancies among women who have cosmetic breast implants be further investigated (18;21;22). Taken as a whole, the epidemiological evidence for risk of cancer at body sites other than the breast, especially for hematopoietic malignancies, needs to be further clarified.
In this updated analysis, 10 more years of follow-up have been added to the largest cohort study carried-out to date on cosmetic breast implants. The considerable number of additional incident breast cancer cases provides opportunities to evaluate breast cancer risk according to implant characteristics over a much longer period of time. Additionally, the assessment of non-breast cancer risk will confirm or verify several of the associations that were observed in our previous analyses. Finally, this analysis provides some comparisons of current results with those of our previous publication of cancer incidence among augmented women (7).
Material and methods
Study design, study population and selection criteria
The study population was described in detail in our previous publication (7). The cohort consisted of women, 18 years of age or older, who were residents of the province of Ontario or Quebec, in Canada, and who underwent bilateral cosmetic breast augmentation (implant group) or received other common elective cosmetic surgeries (controls/comparison group) in their province of residence between January 1, 1974, and December 31, 1989. Other cosmetic surgeries included the following: chemical peel or dermabrasion, coronal brow lift (eyebrow and forehead lift), otoplasty (ear surgery), rhinoplasty (nose surgery), rhytidectomy (face-lift), or blepharoplasty (eyelid surgery). Implant women were frequency matched to other plastic surgery patients by year of entry into the cohort, province of residence and by surgeon.
Ineligible subjects, for both the implant and control groups, were women who had undergone any previous major breast surgery, including reduction mammaplasty, breast lift, and breast cancer surgery. We also excluded women who received other types of silicone or artificial implants, or had a male genotype, or had a history of cancer (excluding nonmelanoma skin cancer) before surgery. Frequency of women excluded for various reasons is documented in our earlier paper (7).
In total, the cohort consisted of 40,451 women: 24,558 received cosmetic breast implants (7,153 women from Ontario and 17,405 from Quebec) and 15,893 women (4,418 from Ontario and 11,475 from Quebec) received other common elective cosmetic surgeries. Information on year of surgery, age at surgery, personal identifying information (used only for linkage purposes) and verification of eligibility criteria for both the implant subjects and the controls and information on implant characteristics such as the type of implant, implant envelope, fill volume and site of implantation, was collected by review of medical (hospital or private clinic) records of all women (implant and control) in the cohort.
The implant and control cohorts were compared to the general population of women. General female population rates of cancer incidence and mortality for the provinces of Ontario and Quebec were obtained from provincial vital and cancer registries (unpublished mortality and cancer tabulations, Chronic Diseases Surveillance and Monitoring Division, Public Health Agency of Canada, Ottawa, 2011).
Ethics approval for the study was granted by the University of Toronto’s Office of Research Ethics, the ethics committee of the Centre Hospitalier Affilié universitaire de Québec’s (CHA) Saint-Sacrement Hospital and the Ethics Committee for Clinical Research of Laval University.
Ascertainment of outcomes
Incident cases of cancer and deaths that occurred from the date of surgery until December 31, 2006 (Quebec) or December 31, 2007 (Ontario) were identified by linking personal identifying information (surname, given and maiden names, mother’s name, father’s name, birth date, residential address and health insurance number) of the cohort members to national and provincial cancer and mortality registries. Specifically, in our previous follow- up (7), cohort members were linked to the Canadian Cancer Registry (CCR) (23) and the Canadian Mortality Database (CMDB) (24) until December 31, 1997. These national registries are managed by Statistics Canada through collaboration with provincial and territorial cancer registries and capture all cancer cases and deaths that occur in Canada and in approximately 20 states in the United-States. The cohort was also linked to cancer incidence data before the index date of surgery, the earliest being 1969. This enabled us to exclude women diagnosed with cancer before their index cosmetic surgeries. Secondly, for this extended follow-up, incident cases of cancer who were diagnosed between January 1, 1998 and December 31, 2006 (Quebec) or December 31, 2007 (Ontario) were identified by linking to provincial registries, namely the Ontario Cancer Registry (OCR) (25) for the Ontario cohort and the Quebec Tumor Registry (QTR) for the Quebec cohort (26). These provincial cancer registries collect information on cancer cases diagnosed in the province corresponding to the cancer registry. The cohort was also linked to provincial mortality databases to identify mortality cases for the period between January 1, 1998 and December
31, 2006 for the Quebec cohort using the mortality file of Quebec held by the Quebec Institute of Statistics and between January 1, 1998 and December 31, 2007 for the Ontario cohort with the use of the Ontario Mortality Database (OMDB) provided by the Registrar General of Ontario. Linkage of the Quebec cohort to the QTR and mortality file was conducted using a deterministic approach while the linkage of the OCR and OMDB to the Ontario cohort was conducted using a probabilistic record linkage system (27). Where no link was found each patient was assumed to be cancer free and alive at the end of follow- up.
Statistical analysis
Person-years of follow-up were calculated for each woman in the breast implant and other cosmetic surgery cohorts from 1 year after the date of surgery until the earliest of date of death, date of cancer diagnosis, December 31, 2006 (Quebec cohort) or December 31, 2007 (Ontario cohort). The first year of follow-up was excluded from analysis, consistent with other investigations (17;18), to reduce the influence that pre-clinically detectable cancers at the time of index cosmetic surgery may have had on our comparisons. The numbers of person-years and incident cases of cancer were tabulated across strata defined by study group (implant or surgical control group), province of residence at the time of index cosmetic surgery (Quebec or Ontario), attained age (18–24, 25–29, 30–34, . . ., 75–79, ≥ 80 years), calendar period of follow-up (1974–1977, 1978–1981, . . .,1994–1997, 1998-2001, 2002-2007), period of surgery (1974–1979, 1980–1984, 1985–1989), age at surgery (18– <30, 30–<40, ≥ 40 years) and time since surgery (1-<5, 5-<10, 10-<15, 15-<20, 20-<25, ≥25 years). Attained age, follow-up interval and time since surgery were time-dependent variables because women would contribute person-years to different categories within these variables as they were followed over time. In contrast, women would contribute person- years to only one level of the classification variables period of surgery and age at surgery. The DATAB module in the Epicure software program was used to calculate person-years of follow-up (28).
The expected numbers of incident cancers in the cohort and the other cosmetic surgeries group were estimated by multiplying the tabulated person-years of follow-up by the
corresponding overall and site-specific cancer rate observed in the general population according to province (Ontario or Quebec), age (by 5-year age intervals), and calendar period of follow-up (1974–1977, 1978–1981, . . ., 1994–1997, 1998-2001, 2002-2007). Differences in cancer incidence rates between the implant and surgical control cohorts relative to the general population were evaluated by calculating the standardized incidence ratio (SIR), which is the ratio of the observed-to-expected number of incident cancers (29). For the comparison with general population estimates, person-years contributed for the period after 1998 were reduced by an interprovincial migration rate according to province, attained age and calendar period of follow-up on the basis of migration rates observed through active follow-up of the Canadian population (30). This was done to account for interprovincial mobility. This approach has been previously applied to reduce the impact of losses to follow-up in a cohort study (31). The 95 percent confidence intervals were calculated for the SIR by assuming that the observed number of incident cancers followed a Poisson distribution, using formulae detailed elsewhere (29). All the p values reported are two sided.
Comparisons of site-specific incident cancer rates between the implant recipients and the other plastic surgery patients, rather than the general population, were done using multivariate Poisson regression models using incidence rate ratios (IRR) as the measure of association (32). We used Cox proportional hazards regression models to evaluate cumulative incidence of breast cancer over the follow-up period (33). The potential confounding influence of the following factors was evaluated: linear and quadratic attained age components, province of residence, calendar period of follow-up, age at surgery, year of surgery and time since surgery. Confounding was examined by a backward deletion approach (34). Specifically, we first adjusted for all potential confounders and then removed one by one in a stepwise manner the least significant confounding variables until the total proportional change in incidence rate ratio estimates compared with those of the fully adjusted model was less than 10 %. Covariates that were not confounders, but increased the precision of the estimates were kept in the final model. To evaluate whether the incidence rate ratio differed by province, a test of homogeneity was conducted by including in the Poisson regression model a first-order interaction term of province and implant status. The 2
provinces were deemed to have different risk estimates if the interaction term was found to be statistically significant based on a two-tailed alpha of <5%. P values for trend of incidence rate ratio over time since surgery were computed, where applicable, using the median time since surgery value for each category as a continuous variable. We included in the regression model a first-order interaction term of this continuous time since surgery variable and the main exposure variable of interest. There was a trend of increasing (or decreasing) incidence rate ratio if the interaction term was found to be statistically significant based on a two-tailed alpha of <5%. For instance, if the main exposure variable is study group (implant vs. controls), a positive and statistically significant interaction term indicates that the incidence rate ratio comparing implant women to controls increases with time since surgery.
Analyses including only women who received breast implants were performed using multivariate Poisson regression models to assess associations of implant characteristics to breast cancer incidence. The following implant characteristics were evaluated: type of implant (silicone gel-filled implants (SGFIs) or and saline), envelope (polyurethane-coated or not), subglandular or submuscular placement, and fill volume. For implant fill volume, women were categorized based on the quartiles of the observed frequency distribution of the mean value of the right and left implants (<175, 175–<200, 200–<225 and ≥ 225 cc) (7). Confounding, trend and interaction were assessed with the same approaches mentioned above. Analyses were done with SAS, version 9.2 (35).
Results
A total of 581,331 and 374,996 person–years of follow-up were accrued in the breast implant (n=24,558) and the other cosmetic surgery (n=15,893) cohorts, respectively (Table 1). The total amount of person-years accrued when the interprovincial migration correction was applied reached 577,257 and 372,532 respectively for the implant group and the other plastic surgery patients (data not shown). The mean duration of follow-up was about the same in the two study groups; 23.7 years for the implant cohort and 23.6 years for the control cohort. Specifically, more than 70% of the women in both the breast implant and other cosmetic surgery cohort were followed for at least 20 years. As reported in our
previous publication, most of women in the breast implant cohort (65.6%) received implants filled with silicone gel (7). The site of implantation was more frequently submuscular (56%) than subglandular (32.6%) (7). Few recipients received implants with a polyurethane foam covered envelope (10.5 %); of those who did, most came from the province of Quebec (7).
A total of 1,521 and 1,220 incident cancers were identified among implant women and other cosmetic surgery women, respectively (Table 2). Comparisons with general female population estimates showed that the observed number for cancers of all sites was significantly lower than the expected number in both the implant cohort (SIR = 0.71, 95% CI = 0.67-0.75) and other cosmetic surgery cohort (SIR = 0.79, 95% CI = 0.74-0.83). Statistically significant reductions in rate of breast cancer were observed in both the implant women (SIR = 0.54, 95% CI= 0.49-0.59) and the control group (SIR = 0.88, 95% CI = 0.80-0.96). As well, significantly lower than expected rates for stomach, colorectal, endometrial, ovary, lymphohematopoietic cancers and all other cancer sites combined were observed among implant women compared to the general female population. There were also reduced risks of colorectal, endometrial, lymphohematopoietic cancers and all other cancer sites combined for the other cosmetic surgery cohort relative to general female population estimates.
Internal comparisons revealed that compared with other cosmetic surgery women, those with breast implants had significantly reduced rates for cancers of all sites (IRR = 0.88, 95% CI= 0.82-0.95), breast (IRR = 0.60, 95% CI= 0.53-0.69), overall genital (IRR = 0.77, 95% CI= 0.63-0.95) and endometrial (IRR = 0.55, 95% CI= 0.38-0.78) cancers (Table 3). However, when removing breast and endometrial cancers from all sites combined, there were little or no differences between implant women and other cosmetic surgery women for overall cancer incidence (IRR = 1.08, 95% CI= 0.94-1.23) (data not shown). As well, when removing endometrial cancers from overall genital cancers, little or no differences were seen between implant women and those with other cosmetic surgeries for overall genital